5-Hydroxyicosatetraenoic acid

5-Hydroxyicosatetraenoic acid
Names
IUPAC name
(5S,6E,8Z,11Z,14Z)-5-Hydroxyicosa-6,8,11,14-tetraenoic acid
Other names
5-HETE, 5(S)-HETE
Identifiers
70608-72-9 N
ChEBI CHEBI:28209 YesY
ChEMBL ChEMBL164813 YesY
ChemSpider 4444314 YesY
3390
Jmol 3D model Interactive image
Interactive image
PubChem 5280733
Properties
C20H32O3
Molar mass 320.47 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

5-Hydroxyicosatetraenoic acid (5-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid, made by a wide variety of cell types of mammals and other species. 5(S)-HETE along with closely related metabolites are hormone-like autocrine and paracrine signalling agents. In these roles, the 5-HETE family metabolites can amplify or dampen inflammation and allergy responses to disturbances in various animal species including humans.

5-HETE is synthesized from 5-HPETE, and while it is pro-inflammatory, it can be used as a precursor to the much more potent pro-inflammatory signalling molecule 5-Oxo-ETE. 5-HETE is also much less potent compared to other eicosanoids such as leukotrienes, which are produced from 5-HPETE by an alternative pathway. Furthermore, it may be metabolized to produce the anti-inflammatory lipoxins.

Nomenclature

5-Hydroxyicosatetraenoic acid is more properly termed 5(S)-hydroxyicosatetraenoic acid (i.e., 5(S)-HETE) to signify the (S) stereochemical configuration of its 5-hydroxy residue as opposed to its 5(R)-hydroxyicosatetraenoic acid (i.e., 5(R)-HETE) stereoisomer. A shortened but still unambiguous version of 5(S)-HETE's IUPAC name is 5S-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid where Z and E signify the cis and trans configurations of its four double bonds.

History of discovery

5-HETE was first described in 1976 as a product made by neutrophils.[1] Several years later it was found to stimulate human neutrophil chemotaxis[2] and a racemic mixture of 5-(S)-HETE and 5(R)-HETE was found to be the most potent stimulator among a series of racemic mono-hydroxy eicosatetraenoates (i.e. HETEs) of human neutrophil aggregation.[3] These effects, it was suggested, may have reflected the ability of 5-(S)-HETE to act through the same Cell surface receptor used by leukotriene B4 (LTB4); LTB4 is also a 5-(S)-hydroxy-eicosateraenoate and has neutrophil chemotactic and aggregating activity that is similar to (but far more potent than) that of 5-(S)-HETE.[4] However, further studies in neutrophils indicated that 5-(S)-HETE had a somewhat different set of actions than LTB4 and acted through a receptor system distinct from that used by LTB4.[5] Subsequent studies identified several other polyunsaturated fatty acid metabolites with key structural similarities to 5-(S)-HETE that operated through this receptor.[6] Thus, 5-(S)-HETE is the first described member of a structurally and functionally related family of metabolites of which its 5-keto analog, 5-oxo-eicosatetraenoic acid (5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid, 5-oxo-ETE, or 5-oxoETE), because of its potency, gives its name to the family's common receptor viz., the Oxoeicosanoid receptor 1 or OXER1.[7]

5-(S)-HETE synthesis

5(S)-HETE is a product of the cellular metabolism of the n-6 Polyunsaturated fatty acid, arachidonic acid, by 5-lipoxygenase (5-LO, 5-LOX, or ALOX5): ALOX5 oxygenates arachidonic acid to Arachidonic acid 5-hydroperoxide, that is to 5-(S)-hydroperoxy-6E,8Z,11Z,14Z-eicosatetraenoate (5-(S)-HpETE). This hydroperoxy product may be further metabolizes to 5(6)-oxido-eicosatetraenoic acid, i.e. Leukotriene A4 and then to either leukotriene B4 by Leukotriene A4 hydrolase or to leukotriene C4 by Leukotriene C4 synthase; this leukotriene C4 may then be further metabolized to Leukotriene D4 and then Leukotriene E4. If not metabolized by these alternative and physiologically important pathways (see Leukotriene B4 and Leukotriene C4), the(S)-HpETE is rapidly reduced by ubiquitous cellular peroxidases to 5-(S)-HETE.[8] The relative amounts of these metabolites made by specific cells and tissues depends upon their content of the appropriate enzymes as well as other conditions.

Distribution of 5-(S)-HETE-synthesizing cells

Human ALOX5 and its 5(S)-HETE synthesizing capacity are considered to be highly expressed primarily in cells that regulate host defense, inflammation, and allergy such as blood-born neutrophils, eosinophils, B lymphocytes, and monocytes, monocyte-derived tissue macrophages, dendritic cells, and the foam cells of atherosclerosis tissues, and tissue mast cells.[9] ALOX5 may also be expressed at relatively low levels in a variety of other cell types but is seems more likely that 5(S)-production in most tissues, such as those of the vasculature, is mediated by the blood and tissue cells just sited.[10] Human prostate, lung, colon, colorectal and pancreatic cancer cells may overexpress ALOX5 as a consequence of their malignant transformation.[11]

Further metabolism of 5-(S-HETE)

One or more cell types may further metabolize 5-(S)-HETE (or its 5(S)HpETE precursor) using: a) acyltransferase-dependent acylation into cellular phospholipids and glycerides; b) 5-Hydroxyeicosanoid dehydrogenase (5-HEDH) to form 5-oxo-eicosatetraenoic acid (i.e. 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoate or 5-oxo-ETE); c) a C-20 hydroxylase cytochrome P450 (probably CYP4F3) to form 5-(S),20-dihydroxy-eicosatetraenoate (5,20-diHETE); d) Arachidonate 15-lipoxygenase-1 (although ALOX15B, i.e. 15-lipoxygenase-2 has not been excluded as a possible mediator of this reaction) to form 5-(S),15-(S)-dihydroxy-eicosatetraenoate (5,15-diHETE); e) 12-lipoxygenase to form 5,12-diHETE; f) cyclooxygenase-2 to form 5-(S),15(R)-diHETE and 5-(S),11(R)-diHETE; and g) aspirin-treated cyclooxygenase-2 to form 5-(S),15(R)-diHETE.[12][13][14][15][16]

During the metabolism of 5-(S)-HpETE by LTA4 hydrolase, the 7-trans,9-trans isomer of 5-oxo-ETE (5-oxo-ETE has 6-trans, 8-cis double bonds), 5-oxo-(7E,9E,11Z,14Z)-eicosatetraenoic acid (7-trans,9-trans-5-oxo-ETE) is produced in small quantities as a byproduct of leukotriene B4 synthesis; it also forms as non-enzymatic hydrolysis of LTA4.[17] 7-Trans,9-trans-5-oxo-ETE stimulates human neutrophils primarily if not exclusive through LTB4 receptors rather than the OXER1, being about 70-fold weaker than LTB4 in doing so.[18]

Alternate pathways that make some of the above described or closely related products include the: a) metabolism of 5(S)-HpETE to 5-oxo-ETE by cytochrome P450 (CYP) enzymes such as CYP1A1, CYP1A2, CYP1B1, and CYP2S1; b) conversion of 5-HETE to 5-oxo-ETE non-enzymatically by heme or other dehydrating agents; c) the formation of 5-oxo-15-(S)-hydroxy-ETE through 5-HEDH-based oxidation of 5-(S),15-(S)-dihydroxyicosatetraenoate; d) formation of 5-(S),15(R)-dihydroxy-eicosatetraenoate by the attack of ALOX5 on 15-hydroxyicosatetraenoic acid (15-(S)-HETE); e) formation of 5-oxo-15-(S)-hydroxy-eicosatetreaenoate (5-oxo-15-(S)-hydroxy-ETE) by the arachidonate 15-Lipoxygenase-1-based or arachidonate 15-lipoxygenased-2-based metabolism of 5-oxo-ETE; and f) the conversion of 5-(S)-HpETE and 5(R)-HpETE to 5-oxo-ETE by the action of a mouse macrophage 50-60 kilodalton cytosolic protein.[19]

As detailed in the 5-oxo-eicosatetraenoic acid page, 5-Oxo-ETE may be metabolized in a fashion like 5(S)-HETE through may of the above described pathways. It can also be rapidly converted back to 5-(S)-HETE by 5-HEDH. 5-HEDH acts reversibly with its favored direction determined by ambient NADPH/NADP+ ratios: cells expressing high ratios of NADPH to NADP+ make little or no 5-oxo-ETE from endogenous or exogenous 5-HETE and rapidly convert exogenous 5-oxo-ETE to 5-(S)-HETE; cells expressing low NADPH to NADP+) ratios convert a sizable portion of 5-(S)-HETE to 5-oxo-ETE. Most 5-(S)-HETE-producing cells such as human neutrophils maintain high NADPH/NADP+ ratios and therefore make little or no 5-oxo-ETE and rapidly convert exogenous 5-oxo-ETE to 5-(S)-HETE; however, aging, apoptotic, and oxidatively stressed 5-(S)-HETE-producing cells use up NADP+ and consequently have NADPH/NADP+ ratios that favor the accumulation of 5-oxo-ETE over 5-(S)-HETE.

Formation of the various metabolites of 5-HETE often involves the combined efforts of different cell types. For example, the 5(S)-HETE made by human polymorphonuclear leukocytes is readily converted to 5-oxo-ETE by human PC3 prostate cancer cells in mixed culture of the two cell types and in an in vitro mixed suspension of neutrophils and platelets 5-oxo-12(S)-hydroxy-eicosatetraenoate is produced from the 5-oxo-ETE made by neutrophils and the 12-hydroxylation of it by platelets. (5-Oxo-12(S)-hydroxy-eicosatetraenoate is a weak inhibitor of 5-oxo-ETE binding and activation of OXER1.) It is suggested that similar events occur in in vivo and are responsible for regulation the production of 5-oxo-ETE and other 5-HETE family agonists.[20]

Mechanism of action

The OXER1 receptor

5-(S)-HETE family members share a common receptor target for stimulating cells that differs from and receptors targeted by the other major products of ALOX5, i.e., leukotriene B4, leukotriene C4, leukotriene D4, leukotriene E4, lipoxin A4, and lipoxin B4; members of the 5-(S)-HETE family stimulate cells primarily by binding and thereby activating a dedicated G protein-coupled receptor, the oxoeicosanoid receptor 1 or OXER1 (also termed OXE, OXE-R, hGPCR48, HGPCR48, or R527 receptor); OXER1's gene is sometimes termed OXE1.[15][21] OXER1 couples to the G protein complex composed of the Gi alpha subunit (Gαi) and G beta-gamma complex (Gβγ); when bound to a 5-(S)-HETE family member, OXER1 triggers this G protein complex to dissociate into its Gαi and Gβγ components with Gβγ appearing to be the component responsible for activating the signal pathways which lead to cellular functional responses.[15] The cell-activation pathways stimulated by OXER1 include those mobilizing ionic calcium and activating MAPK/ERK, p38 mitogen-activated protein kinases, cytosolic Phospholipase A2, PI3K/Akt, and protein kinase C beta and epsilon.[15][22]

Other GPCR receptors

Mouse MA-10 cells respond to 5-oxo-ETE but lack OXER1. It has been suggested that these cells' responses to 5-oxo-ETE are mediated by an ortholog to OXER1, mouse niacin receptor 1, Niacr1, which is a G protein-coupled receptor for niacin, or, alternatively, by one or more of the mouse hydroxycarboxylic acid (HCA) family of the G protein-coupled receptors, HCA1 (GPR81), HCA2 (GPR109A), and HCA3 (GPR109B), which are G protein-coupled receptors for fatty acids.[23]

The PPARγ receptor

5-Oxo-15(S)-hydroxy-ETE and to a lesser extent 5-oxo-ETE but not 5-(S)-HETE also bind to and activate peroxisome proliferator-activated receptor gamma (PPARγ). This activation does not proceed through OXER1; rather, it involves the direct binding of the oxo analogs to PPARγ with 5-oxo-15-(S)-HETE being more potent in binding and activating PPARγ.[24] Activation of OXER1 receptor and PPARγ by the oxo analogs can have opposing effects on cell function. For example, 5-oxo-ETE-bound OXER1 stimulates whereas 5-oxo-ETE-bound PPARγ inhibits the proliferation of various types of human cancer cell lines; this results in 5-oxo-ETE and 5-oxo-15-(S)-HETE having considerably less potency than anticipated in stimulating these cancer cells to proliferate relative to the potency of 5-(S)-HETE, a relationship not closely following the potencies of these three compounds in activating OXER1.[24]

Other mechanisms

5-(S)-HETE acylated into the phosphatidylethanolamines fraction of human neutrophil membranes is associated with the inhibition of these cells from forming neutrophil extracellular traps, i.e. extracellar DNA scaffolds which contain neutophil-derived antimicrobial proteins that circulate in blood and have the ability to trap bacteria.[25] It seems unlikely that this inhibition reflects involvement of OXER1.

5-Oxo-ETE relaxes pre-contracted human bronchi by a mechanism that does not appear to involve OXER1 but is otherwise undefined.[22][26]

Potencies of 5-HETE family members and metabolites

The potencies of 5-(S)-HETE family members in stimulating most cell types that express OXER1 are primarily a function of their affinities for OXER1. Assuming a potency of 100 for 5-oxo-ETE, the potencies of 5-oxo-15(S)-HETE, 5-(S)-HETE, 5-(S),15-(S)-dihete, 5-oxo-20-hydroxy-ETE, 5-(S),20-diHETE, 5,15-dioxo-ETE, and 5(R)-HETE are about 30, 5-10, 1-3, 1-3, 1, <1, and 0-3, respectively, in stimulating human neutrophils; the potencies of these agents have been shown or anticipated to correlate closely with their ability to bind with the OXER1 receptor in human neutrophil plasma membrane preparations and to stimulate other types of OXER1-bearing cells.[22][27][28]

Other metabolites of polyunsaturated fatty acids that belong to the 5-oxo-ETE family by virtue of their ability to stimulate cells through OXER1 include: 5(S)-hydroxyl-6E,8Z,11Z-eicosatrienoic acid and 5(S)-oxo-6E,8Z,11Z-eicosatrienoic acid (5-lipoxygenase metabolites of mead acid), and 5(S)-hydroxy-6E,8Z,11Z,14Z,17Z-eicosapentaenoic acid and 5-oxo-6E,8Z,11Z,14Z,17Z-eicosapentaenoic acid (5-LO metabolites of the eicosapentaenoic acid). The 5-oxo metabolite of mead acid is almost as potent as, and the 5-oxo metabolite of eicosapentaenoic acid is ~10-fold weaker than, 5-oxo-ETE. These metabolites could have a physiological role in activating OXER1-bearing cells in vivo.[29] Human neutrophils metabolize sebaleic acid (5Z,8Z-octadecadienoic acid), a component of sebum secreted by human sebaceous glands of the skin, to a) 5(S)-hydroxy-6E,8Z-octadecadienoic (5(S)-HODE or 5-HODE), b) 5(S)-oxo-6E,8Z-octadecadienoic acid (5-oxo-ODE), c 5(S),18-dihydroxy-6E,8Z-octadecaenoic acid (5(S),18-diHODE or 5,18-diHODE), and d 5-oxo-18-hydroxy-octadecaenoic acid (5-oxo-18-HODE) (the chirality at the 18-hydroxy position of the latter two compounds has not been determined). Human skin keratinocytes also convert 5-HODE to 5-oxo-ODE. 5-Oxo-ODE is almost as potent as 5-oxo-ETE in stimulating human neutrophils and appears to act through OXER1; 5-HODE and 5-oxo-18-HODE are ~10-fold less potent in doing so; and 5,18-diHODE is relatively inactive. It is suggested that the first three of these sebaleic acid metabolites, particularly 5-oxo-ODE, may be involved in inflammatory responses that occur in human skin. However, none of these metabolites, including those of mead and eicosapentaenoic acids, have yet been identified in vivo nor evaluated in pre-clinical or clinical studies.[22][30]

5-Oxo-18-hydroxy-eicosatetraeonic acid (5-oxo-18-HETE), 5(S),18-dihydroxy-eicosatetraenoic acid (5(S),18-diHETE), 5-oxo-18-hydroxy-eicosatrienoic acid (5-oxo-18-HETrE), 5(S),18-dihydroxy-eicosatreineoic acid (5(S)-diHETrE), 5-oxo-19-hydroxy-eicosatetraenoic acid (5-oxo-18-HETrE), 5(S),19-dihydroxy-eicosatetreaenoic acid (5(S)-19-HETE), and 5-oxo-19-hydroxy-eicosatrienoic acid (5-oxo-19-HETrE) are essentially inactive in stimulating human neutophils.[31] Based on these potency assignments, the conversion of 5-(S)-HETE to 5-oxo-ETE serves an activating function while 5-oxo-ETE's reduction to 5-(S)-HETE serves am inactivating function; hydroxylation at carbon 20 (i.e. ω-oxidation) serves to inactivate 5-oxo-ETE and 20-HETE, and 5-(S),15-(S)-diHETE, 5-oxo-20-hydroxy-ETE, 5-(S),20-diHETE, 5,15-dioxo-ETE, 5(R)-HETE, 5-Oxo-18-HETE, 5,18-diHETE, 5-oxo-18-HETrE, 5,18-diHETrE, 5-oxo-19-HETE, 5,19-diHETE, and 5-oxo-19-HETrE would appear to have little or no role in the physiological activation of cells through OXER1. 5-Oxo-12-hydroxy-ETE is also inactive in stimulating neutrophils and actually is a weak (and therefore unlikely to be a physiologically relevant) inhibitor these cells responses to 5-oxo-ETE.[22]

The 5-HETE and 5-oxo-ETE that are acylated to cellular glycerolipids have not been assigned a direct role in cell function. Since these metabolites may be released from phospholipids during cell stimulation, their acylation into phospholipids may serve as a storage pool which is readily mobilized during cell activation.[22]

Clinical significance

Inflammation

5(S)-HETE and other family members were first detected as products of arachidonic acid made by stimulated human polymorphonuclear neutrophils (PMN), a leukocyte blood cell type involved in host immune defense against infection but also implicated in aberrant pro-inflammatory immune responses such as arthritis; soon thereafter they found to be active also in stimulating these cells to migrate (i.e. chemotaxis), degranulate (i.e. release the anti-bacterial and tissue-injuring contents of their granules), produce bacteriocidal and tissue-injuring reactive oxygen species, and mount other pro-defensive as well as pro-inflammatory responses of the Innate immune system. For example, the gram-negative bacterium, Salmonella tryphimurium, and the outer surface of gram negative bacteria, Lipopolysaccharide, promote the production of 5-(S)-HETE and 5-oxo-ETE by human neutrophils. The family members stimulate another blood cell of the innate immunity system, the human monocyte, acting synergistically with the pro-inflammatory CC chemokines, monocyte chemotactic protein-1 and monocyte chemotactic protein-3, to stimulate monocyte function. 5-Oxo-ETE also stimulates two other cell types that share responsibility with the PMN for regulating inflammation, the human lymphocyte and dendritic cell. And, in in vivo studies, the injection of 5-oxo-ETE into the skin of human volunteers causes the local accumulation of PMN and monocyte-derived macrophages.[22] Furthermore, the production of one or more 5(S)-HETE family members as well as the expression of orthologs of the human OXER1 receptor occur in various mammalian species including dogs, cats, cows, sheep, elephants, pandas, opossums, and ferrets and in several species of fish; for example, cats undergoing experimentally induced asthma accumulate 5-oxo-ETE in their lung lavage fluid, feline leucocytes make as well as respond to 5-oxo-ETE by an oxer1-dependent mechanism; and an OXER1 ortholog and, apparently, 5-oxo-ETE are necessary for the inflammatory response to tissue damage caused by osmolarity insult in zebrafish.[20][32][33]

These results given above suggest that members of the 5-oxo-ETE family and the OXER1 receptor or its orthologs may contribute to protection against microbes, the repair of damaged tissues, and pathological inflammatory responses in humans and other animal species.[20] However, an OXER1 ortholog is absent in mice and other rodents; while rodent tissues do exhibit responsiveness to 5-oxo-ETE, the lack of an oxer1 or other clear 5-oxoETE receptor in such valued animal models of diseases as rodents has impeded progress in our understanding of the physiological and pathological roles of 5-oxo-ETE.[33]

Allergy

The following human cell types or tissues that are implicated in allergic reactivity produce 5-HETE (stereoisomer typically not defined): alveolar macrophages isolated from asthmatic and non-asthmatic patients, basophils isolated from blood and challenged with anti-IgE antibody, mast cells isolated from lung, cultured pulmonary artery endothelial cells, isolated human pulmanary vasculature, and allergen-sensitized human lung specimens challenged with specific allergen.[22][34] Additionally, cultured human airway epithelial cell lines, normal bronchial epithelium, and bronchial smooth muscle cells convert 5-(S)-HETE to 5-oxo-ETE in a reaction that is greatly increase by oxidative stress, which is a common component in allergic inflammatory reactions.[22] Finally, 5-HETE is found in the bronchoalveolar lavage fluid of asthmatic humans and 5-oxo-ETE is found in the bronchoalveolar lavage fluid of cats undergoing allergen-induced bronchospasm.[22][33][35]

Among the 5-HETE family of metabolites, 5-oxo-ETE is implicated as the most likely member to contribute to allergic reactions. It has exceptionally high potency in stimulating the chemotaxis, release of granule-bound tissue-injuring enzymes, and production of tissue-injuring reactive oxygen species of a cell type involved in allergic reactions, the human eosinophil granulocyte.[22] It is also exceptionally potent in stimulating eosinophils to activate cytosolic phospholipase A2 (PLA2G4A) and possibly thereby to form platelet-activating factor (PAF) as well as metabolites of the 5-HETE family.[22][36] PAF is itself a proposed mediator of human allergic reactions which commonly forms concurrently with 5-HETE family metabolites in human leukocytes and acts synergistically with these metabolites, particularly 5-oxo-ETE, to stimulate eosinophils.[22][37][38][39] 5-Oxo-ETE also cooperates positively with at least four other potential contributors to allergic reactions, RANTES, Eotaxin, Granulocyte macrophage colony-stimulating factor, and granulocyte colony-stimulating factor in stimulating human eoxinophils and is a powerful stimulator of chemotaxis in another cell type contributing to alleric reactions, the human basophil granulocyte.[22] Finally, 5-oxo-ETE stimulates the infiltration of eosinophils into the skin of humans following its intradermal injection (its actions are more pronounced in asthmatic compared to healthy subjects) and when instilledd into the trachea of Brown Norway rats causes eosinophils to infiltrate lung.[22] These results suggest that the 5-oxo-ETE made at the initial tissue site of allergen insult acting through the OXER1 on target cells attracts circulating eosinophils and basophils to lung, nasal passages, skin, and possibly other sites of allergen deposition to contribute to asthma, rhinitis, and dermatitis, and other sites of allergic reactivity.[22][40]

The role of 5-HETE family agonists in the bronchoconstriction of airways (a hallmark of allergen-induced asthma) in humans is currently unclear. 5-HETE stimulates the contraction of isolated human bronchial muscle, enhances the ability of histamine to contract this muscle, and contracts guinea pig lung strips.[41] 5-Oxo-ETE also stimulates contactile responses in fresh bronchi, cultured bronchi, and cultured lung smooth muscle taken from guinea pigs but in direct contrast to these studies is reported to relax bronchi isolated from humans.[42][43][44] The latter bronchi contractile responses were blocked by cyclooxygenase-2 inhibition or a thromboxine A2 receptor antagonist and therefore appear mediated by 5-oxo-ETE-induced production of this thromboxane. In all events, the relaxing action of 5-oxo-ETE on human bronchi does not appear to involve OXER1.[22]

Cancer

The 5-oxo-ETE family of agonists have also been proposed to contribute to the growth of several types of human cancers. This is based on their ability to stimulate certain cultured human cancer cell lines to proliferate, the presence of OXER1 mRNA and/or protein in these cell lines, the production of 5-oxo-ETE family members by these cell lines, the induction of cell death (i.e. apoptosis) by inhibiting 5-lipoxygenase in these cells, and/or the overexpression of 5-lipoxygenase in tissue taken form the human tumors. Human cancers whose growth has been implicated by these studies as being mediated at least in part by a member(s) of the 5-oxo-ETE family include those of the prostate, breast, lung, ovary, and pancreas.[22][45][46][47]

Steroid production

5-(S)-HETE and 5-(S)-HpETE stimulate the production of progesterone by cultured rat ovarian glomerulosa cells[48] and enhance the secretion of progesterone and testosterone by cultured rat testicular Leydig cells.[49] Both metabolites are made by Cyclic adenosine monophosphate-stimulated MA-10 mouse leydig cells; stimulate these cells to transcribe Steroidogenic acute regulatory protein, and in consequence produce the steroids.[50][51] The results suggest that trophic hormones (e.g., leutenizing hormone, adrenocorticotropic hormone) stimulate these steroid producing cells to make 5-(S)-HETE and 5-(S)HpEPE which in turn increase the synthesis of steroidogenic acute regulatory protein; the latter protein promotes the rate-limiting step in steroidogenesis, transfer of cholesterol from the outer to the inner membrane of mitochondria and thereby acts in conjunction with trophic hormone-induce activation of protein kinase A to make progesterone and testosterone.[52] This pathway may also operate in humans: Human H295R adrenocortical cells do express OXER1 and respond to 5-oxo-ETE by an increasing the transcription of steroidogenic acute regulatory protein messenger RNA as well as the production of aldosterone and progesterone by an apparent OXER1-dependent pathway.[53]

Rat and mouse cells lack OXER1. It has been suggested that the cited mouse MA-10 cell responses to 5-oxo-ETE are mediated by an ortholog to OXER1, mouse niacin receptor 1, Niacr1, which is a G protein-coupled receptor mediating the activity of niacin, or by one or more of the mouse hydroxycarboxylic acid (HCA) family of the G protein-coupled receptors, HCA1 (GPR81), HCA2 (GPR109A), and HCA3 (GPR109B), which are G protein-coupled receptors for fatty acids.[53] In any event, Human H295R adrenocortical cells do express OXER1 and respond to 5-oxo-ETE by an increasing the transcription of steroidogenic acute regulatory protein messenger RNA as well as the production of aldosterone and progesterone by an apparent OXER1-dependent pathway.[53]

Bone remodeling

In an in vitro mixed culture system, 5-(S)-HETE is released by monocytes to stimulate, at sub-nanamolar concentrations, osteoclast-dependent bone reabsorption.[54] It also inhibits morphogenetic protein-2 (BMP-2)-induced bone-like nodule formation in mouse calvarial organ cultures.[55] These results allow that 5-(S)-HETE and perhaps more potently, 5-oxo-ETE contribute to the regulation of bone remodeling.

Parturition

5(S)-HETE) is: elevated in the human uterus during labor;[56] at 3-150 nM, increases both the rates of spontaneous contractions and overall contractility of myometrial strips obtained at term but prior to labor from human lower uterine segments;[57] and in an in vitro system crosses either amnion or intact amnion-chorion-decidua and thereby maym along with prostaglandin E2 move from the amnion to uterus during labor in humans.[58] These studies allow that 5(S)-HETE, perhaps in cooperation with established role of prostaglandin E2, may play a role in the onset of human labor.

Other actions

5(S)-HETE is reported to modulate tubuloglomerular feedback.[59] 5(S)-HpETE is also reported to inhibit the Na+/K+-ATPase activity of Synaptosome membrane preparations prepared from ratcerebral cortex and may thereby inhibit synapse-dependent communications between neurons.[60]

5(S)-HETE acylated into phosphatidylethanolamine is reported to increase the stimulated production of superoxide anion and interlukin-8 release by isolated human neutrophils and to inhibit the formation of Neutrophil extracellular traps (i.e. NETS); NETS trap blood-circulating bacteria to assist in their neutralization).[61] 5(S)-HETE esterified to phosphatidylcholine and glycerol esters by human endothelial cells is reported to be associated with the inhibition of prostaglandin production.[62]

Possible alternative receptor

Progress in proving the role of the 5-HETE family of agonists and their OXER1 receptor in human physiology and disease has been made difficult because mice and rats, which are the most common in vivo models for investigating these issues, lack OXER1; this receptor is expressed in non-human primates and a wide range of other mammals as well as various species of fish but not in the rodents so far tested.[22] A model of allergic airways disease in cats, which express OXER1 and make 5-oxo-ETE has recently been developed for such studies.[33]

The mouse ortholog of the human Niacin receptor 1 (NIACR1), Niacr1, has been proposed to mediate the action of 5-oxo-ETE on mouse Leydig cells.[63] The roles, if any, of Niacr1 in the response of these leydig cells to other 5-HETE family members as well as in the response of other mouse cells and tissues to 5-HETE family members and the role of Niacr1 orthologs in the response of human and other species tissues to 5-HETE family members has not been determined.

See also

References

  1. ↑ "Transformation of arachidonic acid and homo-gamma-linolenic acid by rabbit polymorphonuclear leukocytes. Monohydroxy acids from novel lipoxygenases". J Biol Chem 251 (24): 7816–20. Dec 1976. PMID 826538.
  2. ↑ "Modulation of human neutrophil function by monohydroxy-eicosatetraenoic acids". Immunology 39 (4): 491–501. Apr 1980. PMC 1458022. PMID 6247265.
  3. ↑ O'Flaherty JT, Thomas MJ, Lees CJ, McCall CE (1981). "Neutrophil-aggregating activity of monohydroxyeicosatetraenoic acids". Am. J. Pathol. 104 (1): 55–62. PMC 1903737. PMID 7258296.
  4. ↑ O'Flaherty JT, Hammett MJ, Shewmake TB, Wykle RL, Love SH, McCall CE, Thomas MJ (1981). "Evidence for 5, 12-dihydroxy-6,8,10,14-eicosatetraenoate as a mediator of human neutrophil aggregation". Biochem. Biophys. Res. Commun. 103 (2): 552–8. doi:10.1016/0006-291x(81)90487-3. PMID 6277309.
  5. ↑ O'Flaherty JT, Jacobson D, Redman J (1988). "Mechanism involved in the mobilization of neutrophil calcium by 5-hydroxyeicosatetraenoate". J. Immunol. 140 (12): 4323–8. PMID 2836511.
  6. ↑ "5-hydroxyicosatetraenoate stimulates neutrophils by a stereospecific, G protein-linked mechanism". J Biol Chem. 268 (20): 14708–14. Jul 1993.
  7. ↑ "Biochemistry, biology and chemistry of the 5-lipoxygenase product 5-oxo-ETE". Prog Lipid Res. 44 (2-3): 154–83. Mar 2005. doi:10.1016/j.plipres.2005.04.002.
  8. ↑ "5-Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1851: 331–339. doi:10.1016/j.bbalip.2014.08.012.
  9. ↑ "5-Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1851: 331–339. doi:10.1016/j.bbalip.2014.08.012.
  10. ↑ "The 5 lipoxygenase system in the vasculature: Emerging role in health and disease". Mol Cell Endocrinol 252 (1-2): 201–6. Jun 2006. doi:10.1016/j.mce.2006.03.038.
  11. ↑ "5-Lipoxygenase Antagonist therapy: a new approach towards targeted cancer chemotherapy". Acta Biochimica et Biophysica Sinica 45: 709–719. doi:10.1093/abbs/gmt064.
  12. ↑ J Immunol. 1986 Nov 15;137(10):3277-83
  13. ↑ Prostaglandins Leukot Essent Fatty Acids. 2005 Sep-Oct;73(3-4):141-62.Review
  14. ↑ "COX-2-dependent and -independent biosynthesis of dihydroxy-arachidonic acids in activated human leukocytes". The Journal of Lipid Research 53: 87–94. doi:10.1194/jlr.M017822.
  15. 1 2 3 4 "Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid.". Biochim Biophys Acta 1851: 340–355. Apr 2015. doi:10.1016/j.bbalip.2014.10.008. PMID 25449650.
  16. ↑ "Lipoxins and aspirin-triggered lipoxins in resolution of inflammation". European Journal of Pharmacology 760: 49–63. doi:10.1016/j.ejphar.2015.03.083.
  17. ↑ Gravel J, Falgueyret JP, Yergey J, Trimble L, Riendeau D (Nov 1993). "Identification of 5-keto-(7E,9E,11Z,14Z)-eicosatetraenoic acid as a novel nonenzymatic rearrangement product of leukotriene A4". Archives of Biochemistry and Biophysics 306 (2): 469–75. doi:10.1006/abbi.1993.1539. PMID 8215451.
  18. ↑ Falgueyret J, Riendeau D (Feb 2000). "LTA(4)-derived 5-oxo-eicosatetraenoic acid: pH-dependent formation and interaction with the LTB(4) receptor of human polymorphonuclear leukocytes". Biochimica et Biophysica Acta 1484 (1): 51–8. doi:10.1016/s1388-1981(99)00198-5. PMID 10685030.
  19. ↑ Powell WS, Rokach J (Apr 2015). "Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid". Biochimica et Biophysica Acta 1851 (4): 340–55. doi:10.1016/j.bbalip.2014.10.008. PMID 25449650.
  20. 1 2 3 "Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid.". Biochim Biophys Acta 1851: 340–355. Apr 2015. doi:10.1016/j.bbalip.2014.10.008. PMID 25449650.
  21. ↑ O'Flaherty JT, Rossi AG (Jul 1993). "5-hydroxyicosatetraenoate stimulates neutrophils by a stereospecific, G protein-linked mechanism". The Journal of Biological Chemistry 268 (20): 14708–14714. PMID 8392058.
  22. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 "The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor.". Prog Lipid Res 52: 651–65. Oct 2013. doi:10.1016/j.plipres.2013.09.001. PMID 24056189.
  23. ↑ Mol Cell Endocrinol. 2013 May 22;371(1-2):71-8
  24. 1 2 O'Flaherty JT, Rogers LC, Paumi CM, Hantgan RR, Thomas LR, Clay CE, High K, Chen YQ, Willingham MC, Smitherman PK, Kute TE, Rao A, Cramer SD, Morrow CS (Oct 2005). "5-Oxo-ETE analogs and the proliferation of cancer cells". Biochimica et Biophysica Acta 1736 (3): 228–236. doi:10.1016/j.bbalip.2005.08.009. PMID 16154383.
  25. ↑ "Esterified eicosanoids are acutely generated by 5-lipoxygenase in primary human neutrophils and in human and murine infection". Blood 117: 2033–2043. doi:10.1182/blood-2010-04-278887.
  26. ↑ Prostaglandins Other Lipid Mediat. 2007 Jun;83(4):311-9.
  27. ↑ "Chemical and biological characterization of oxo-eicosatetraenoic acids.". Biochim Biophys Acta. 1201 (3): 505–15. Dec 1994. doi:10.1016/0304-4165(94)90083-3. PMID 7803484.
  28. ↑ "Receptors for the 5-oxo class of eicosanoids in neutrophils.". J Biol Chem. 273 (49): 32535–41. Dec 1998. doi:10.1074/jbc.273.49.32535. PMID 9829988.
  29. ↑ Powell WS, Rokach J (Oct 2013). "The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor". Progress in Lipid Research 52 (4): 651–665. doi:10.1016/j.plipres.2013.09.001. PMID 24056189.
  30. ↑ "Human Neutrophils Convert the Sebum-derived Polyunsaturated Fatty Acid Sebaleic Acid to a Potent Granulocyte Chemoattractant". Journal of Biological Chemistry 283: 11234–11243. doi:10.1074/jbc.M709531200.
  31. ↑ J Pharmacol Exp Ther. 2001 Feb;296(2):293-305
  32. ↑ Enyedi B, Kala S, Nikolich-Zugich T, Niethammer P (Sep 2013). "Tissue damage detection by osmotic surveillance". Nature Cell Biology 15 (9): 1123–1130. doi:10.1038/ncb2818. PMC 3826879. PMID 23934216.
  33. 1 2 3 4 "Biosynthesis and actions of 5-oxoeicosatetraenoic acid (5-oxo-ETE) on feline granulocytes". Biochemical Pharmacology 96: 247–255. doi:10.1016/j.bcp.2015.05.009.
  34. ↑ "5-Oxo-ETE and the OXE receptor". Prostaglandins 89: 98–104. doi:10.1016/j.prostaglandins.2009.05.002.
  35. ↑ Am J Respir Crit Care Med. 1994 Apr;149(4 Pt 1):953-9
  36. ↑ O'Flaherty JT, Kuroki M, Nixon AB, Wijkander J, Yee E, Lee SL, Smitherman PK, Wykle RL, Daniel LW (Jul 1996). "5-Oxo-eicosatetraenoate is a broadly active, eosinophil-selective stimulus for human granulocytes". Journal of Immunology 157 (1): 336–342. PMID 8683135.
  37. ↑ "Platelet activating factor. Stimulation of the lipoxygenase pathway in polymorphonuclear leukocytes by 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine". J. Biol. Chem. 257: 5402–5407. 1982. PMID 6802816.
  38. ↑ "1-O-alkyl-2-acyl-sn-glycero-3-phosphocholine: a novel source of arachidonic acid in neutrophils stimulated by the calcium ionophore A23187". Biochem. Biophys. Res. Commun. 113: 72–79. 1983. doi:10.1016/0006-291x(83)90433-3. PMID 6407484.
  39. ↑ "5-Lipoxygenase products modulate the activity of the 85-kDa phospholipase A2 in human neutrophils.". J. Biol. Chem. 270: 26543–26549. 1995. doi:10.1074/jbc.270.44.26543. PMID 7592874.
  40. ↑ "Pharmacotherapy of diseases mediated by 5-lipoxygenase pathway eicosanoids". Prostaglandins Other Lipid Mediat 83 (3): 188–97. May 2007. doi:10.1016/j.prostaglandins.2007.01.005.
  41. ↑ "The actions of 5-, 12-, and 15-HETE on tracheobronchial smooth muscle". Prostaglandins Leukot Med. 8 (2): 105–14. Feb 1982. doi:10.1016/s0262-1746(82)80002-4. PMID 6952280.
  42. ↑ Prostaglandins Other Lipid Mediat. 2007 Jun;83(4):311-9
  43. ↑ "Effects of 5-oxo-ETE and 14,15-EET on reactivity and Ca2+ sensitivity in guinea pig bronchi". Prostaglandins Other Lipid Mediat 82 (1-4): 30–41. Jan 2007. doi:10.1016/j.prostaglandins.2006.05.012.
  44. ↑ "Glucocorticoid-stimulated lung epithelial Na + transport is associated with regulated ENaC and sgk1 expression". Am J Physiol Lung Cell Mol Physiol 287 (4): L631–40. Oct 2004. doi:10.1152/ajplung.00085.2001.
  45. ↑ Avis IM, Jett M, Boyle T, Vos MD, Moody T, Treston AM, Martínez A, Mulshine JL (Feb 1996). "Growth control of lung cancer by interruption of 5-lipoxygenase-mediated growth factor signaling". The Journal of Clinical Investigation 97 (3): 806–813. doi:10.1172/JCI118480. PMC 507119. PMID 8609238.
  46. ↑ Ding XZ, Tong WG, Adrian TE (2003). "Multiple signal pathways are involved in the mitogenic effect of 5(S)-HETE in human pancreatic cancer". Oncology 65 (4): 285–294. doi:10.1159/000074640. PMID 14707447.
  47. ↑ "5-Oxo-ETE analogs and the proliferation of cancer cells.". Biochim Biophys Acta. 1736 (3): 228–36. Oct 2005. doi:10.1016/j.bbalip.2005.08.009. PMID 16154383.
  48. ↑ "Stimulation of progesterone and prostaglandin E 2 production by lipoxygenase metabolites of arachidonic acid". FEBS Lett. 244 (1): 154–8. Feb 1989. doi:10.1016/0014-5793(89)81182-2.
  49. ↑ "Arachidonic acid metabolites as intratesticular factors controlling androgen production". Int J Androl 16 (3): 227–33. Jun 1993. doi:10.1111/j.1365-2605.1993.tb01184.x.
  50. ↑ "Involvement of 5-lipoxygenase metabolites of arachidonic acid in cyclic AMP-stimulated steroidogenesis and steroidogenic acute regulatory protein gene expression". J Steroid Biochem Mol Biol. 85 (2-5): 159–66. Jun 2003. doi:10.1016/s0960-0760(03)00189-4. PMID 12943700.
  51. ↑ "The Role of Arachidonic Acid in Steroidogenesis and Steroidogenic Acute Regulatory (StAR) Gene and Protein Expression". J. Biol. Chem. 275: 20204–20209. 2000. doi:10.1074/jbc.m003113200.
  52. ↑ "Interaction between arachidonic acid and cAMP signaling pathways enhances steroidogenesis and StAR gene expression in MA-10 Leydig tumor cells". Mol Cell Endocrinol 188 (1-2): 55–63. Feb 2002. doi:10.1016/S0303-7207(01)00748-1.
  53. 1 2 3 "Expression and function of OXE receptor, an eicosanoid receptor, in steroidogenic cells.". Mol. Cell. Endocrin 371: 71–78. 2013. doi:10.1016/j.mce.2012.11.003. PMID 23159987.
  54. ↑ "5-Lipoxygenase metabolites of arachidonic acid stimulate isolated osteoclasts to resorb calcified matrices". J Biol Chem 268 (14): 10087–94. May 1993.
  55. ↑ "5-Lipoxygenase Metabolites Inhibit Bone Formation in Vitro". Endocrinology 139 (7): 3178–84. Jul 1998. doi:10.1210/en.139.7.3178.
  56. ↑ "Measurement of vasoactive metabolites (hydroxyeicosatetraenoic and epoxyeicosatrienoic acids) in uterine tissues of normal and compromised human pregnancy". J Hypertens 28 (12): 2429–37. Dec 2010. doi:10.1097/HJH.0b013e32833e86aa. PMID 20852449.
  57. ↑ "The effects of lipoxygenase metabolites of arachidonic acid on human myometrial contractility". Prostaglandins 33 (6): 837–44. Jun 1987. doi:10.1016/0090-6980(87)90112-2.
  58. ↑ "Mechanisms of parturition: The transfer of prostaglandin E2 and 5-hydroxyeicosatetraenoic acid across fetal membranes". Am J Obstet Gynecol 162 (3): 683–7. Mar 1990. doi:10.1016/0002-9378(90)90984-F.
  59. ↑ Walter F., PhD. Boron (2005). Medical Physiology: A Cellular And Molecular Approach. Elsevier/Saunders
  60. ↑ Biochem Biophys Res Commun. 1997 Jun 18;235(2):374-6
  61. ↑ Blood. 2011 Feb 10;117(6):2033-43
  62. ↑ Biochim Biophys Acta. 1986 Feb 28;875(3):569-81
  63. ↑ Cooke M, Di Cónsoli H, Maloberti P, Cornejo Maciel F (May 2013). "Expression and function of OXE receptor, an eicosanoid receptor, in steroidogenic cells". Molecular and Cellular Endocrinology 371 (1–2): 71–8. doi:10.1016/j.mce.2012.11.003. PMID 23159987.

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